The importance of altered beta cell function in the primary pathophysiology of non-insulin dependent diabetes is uncertain. While it is widely recognized that subjects with overt hyperglycemia due to NIDDM have substantial abnormalities in beta cell function, it is uncertain whether these defects play a primary pathophysiologic role in the development of the diabetic syndrome or whether they are secondary to the elevation in glucose and/or the presence of insulin resistance. A key issue in resolving this question is to determine whether beta cell function is normal or abnormal in subjects with mild glucose intolerance who have a high risk of developing overt NIDDM but who are not yet diabetic. The proposed studies aim to test the hypothesis that states of glucose intolerance are characterised by: 1) alterations in the relationships between glucose and insulin sercretion; 2) reduced insulin secretory responses to non-glucose secretogogues, which act at different points in the insulin secretory cascadem and 3) reductions in the ability of the beta cell to adapt normally to the presence of insulin resistance or mild hyperglycemia. Studies will also be performed to determine the extent to which these defects are reversible by treatment of the glucose intolerance and whether the absence of regular oscillations in peripheral insulin reduces the effectiveness of secreted insulin thereby aggravating the state of insulin resistance which is present in many subjects with impaired glucose intolerance and NIDDM. In this context we will specifically determine whether insulin is more efficient in lowering plasma glucose levels when administered as a series of regular oscillations every 120 min rather than at a constant rate.